Telomere dysfunction is a major determinant of aging, degenerative diseases and cancer. In cancer, the telomeres and telomerase have been shown to play critical roles in the initiation and progression of malignancy. Telomere dysfunction, coupled with deactivated p53 checkpoints, enables genome instability and the development and progression of cancer, including metastasis. Significant effort in the current grant has been elucidating the wiring of the p53-dependent telomere checkpoint response and how p53 downstream targets promote degenerative conditions and enable malignant progression. Building on our ongoing work, this renewal will address two important areas of study. First area focuses on two critical targets of the p53 pathway. Work from current funding period from my laboratory has identified a profound deficiency in mitochondria biogenesis and function in telomere dysfunctional mice which results from p53-directed repression of PGC11/2 transcriptional coactivators, the master regulators of mitochondrial biogenesis and p53-directed activation of Quaking (QK), a RNA binding protein which we show is a potent tumor suppressor and regulator of microRNA-directed control of the key mitochondrial regulator, PPARa. These observations have led to the hypothesis that mitochondriopathy and associated energy loss is the primary cause of age related maladies in telomere dysfunctional mice and may dictate certain metabolic responses in cancer cells. The objectives of this competitive renewal will be to genetically assess the telomere-mitochondria link in aging and cancer. The specific efforts focus on (i) the use of an inducible telomerase model (TERT-ER) to assess the regenerative impact on mitochondrial biology and degenerative phenotypes in stem cells and diverse post-mitotic organ systems in aged telomere dysfunction mice;(ii) to genetically define the importance of the PGC11/2 and QK targets as critical mediators of the telomere checkpoint response with respect to mitochondria biology, degenerative aging, and the genesis and progression of cancer and cancer genomic changes. Second area speaks to translation of the concept of anti-telomerase therapy. Our previous work has suggested that anti-telomerase therapy should preferentially avoid patients with p53-deficient tumors. In this renewal, we will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms on the genomic and metabolic levels to anti-telomerase therapy. The identification of these mechanisms should lead to new drugs that may synergize with anti-telomerase therapy. PUBLIC HEALTH RELEVANCE: Telomere dysfunction is one of the hallmark of aging, degenerative diseases and cancer. We will validate the principal of telomerase extinction as an anti-cancer therapy and define potential resistance mechanisms which should lead to new drugs that may synergize with anti-telomerase therapy.